PROJECT: JTC2021 - Neurodevelopmental Disorders: DevInDS

Altered brain excitatory/inhibitory (E/I) balance was proposed to underlie developmental disorders involving intellectual disability and autism spectrum disorder (ASD). Down syndrome (DS), caused by trisomy of human chromosome 21, is characterized by both cognitive deficits and other comorbidities such as ASD. DS subjects exhibit E/I imbalance, but the contribution of specific cortical inhibitory circuits is unknown. We hypothesize that distinct developmental molecular alterations of perisomatic and dendritic inhibitory circuits underlie defective synaptic integration, network desynchronization and thus cognitive and sociability deficits in DS. In this project, we will define interneuron (IN) type-specific identities during pre- and post-natal development in mouse models of DS and, importantly, in human DS brains (prenatal and young adult). We will use single-cell transcriptomics and assess IN migration in DS. These approaches will be combined with ex vivo and in vivo functional investigations in DS mice to probe the activity of specific neuronal circuits at the cellular, microcircuits and network levels. Behavioral tests in mice will be combined with pharmacology and pharmacogenetics to manipulate the activity of specific cortical inhibitory circuits. We aim to pinpoint inhibitory circuit-specific pathophysiological mechanisms and molecular pathways underlying ASD and cognitive deficits in DS, leading to potential novel pharmacological targets.